The objective of this proposal is to develop clinically viable strategies for the quantitative estimation of myocardial blood flow (MBF) from dynamic computed tomography (CT) imaging with low radiation doses comparable to those received in common nuclear myocardial perfusion studies. Despite the proven clinical value of quantifying MBF (in ml/g/min), there are no widespread clinical methods to easily measure MBF in absolute units. Dynamic CT offers the potential to quantify flow, but the radiation dose imparted from these studies prohibits widespread acceptance. The specific aims of the proposal are to develop 1) optimal myocardial blood flow estimation methods, 2) low-dose dynamic CT acquisition strategies for MBF estimation, 3) unbiased data restoration algorithms and 4) image reconstruction methods based on trading off spatial resolution for noise reduction and constraining noise with a priori knowledge. These aims will be developed with simulations of dynamic contrast enhanced CT imaging and evaluated with patient exams. We hypothesize that accurate subendo- and subepi-cardial MBF estimates can be determined with low- dose dynamic CT through selection of acquisition strategies and judicious application of noise reduction strategies. This work proposes novel low-dose acquisition and data/image enhancement strategies to enable accurate quantitative estimates of blood flow in absolute units of ml/g/min. These methods will allow for substantial reductions in radiation dose, which is essential for patient safety, clinical application of dynamic CT for MBF measurement, and for other proven applications of dynamic CT. This work will position cardiac dynamic CT as a safe, easy, and widely available tool for quantitative MBF estimation, providing valuable clinical information for quantification of flow limiting disease, minimizing unnecessary catheterization procedures, informing therapy choices, and developing new therapies.